Abstract
Brain metastases are about ten times more frequent than a brain primary tumor, being present in 20-40% of adults with systemic cancer. Together with lung cancer and breast cancer, skin cancers such as melanoma are top primary tumors which metastasizes to the brain. Advanced melanoma is well known for its propensity to metastasize to the brain, with 80% of patients presenting brain metastasis at the autopsy. However, current therapies are not very efficient and brain metastases are in most of the cases lethal. Treatment of melanoma brain metastases with surgery and/or radiation therapy results in a median overall survival of only about four months after diagnosis. New immunotherapies such as targeted or immunomodulatory drugs, many in clinical trials, have shown promise, with some immunomodulatory drugs being able to at least double the overall survival rates for patients with melanoma brain metastases. This review focuses on the recent advances and future potential of using immunotherapy, such as the newly developed immunomodulatory drugs, for melanoma brain metastases therapy. Immunomodulatory drugs bring a great promise as new tools for melanoma treatment in particular and for the treatment of other types of malignancies in general.
Keywords: Immunotherapy, Immune Checkpoint Inhibitors, PD-1, PD-L1, CTLA-4; BRAF inhibitor; melanoma; brain metastases.
SUMMARY
1. Introduction
2. Melanoma Brain Metastasis
3. Current Treatments in Melanoma Brain Metastasis
4. Immunotherapy in Metastatic Melanoma Tumors
5. Challenges and Limitations
6. Conclusion
1. Introduction
Brain metastasis, the spread of a tumor from a primary neoplasm to the brain, is about 10 times more frequent than a primary brain tumor1. Noteworthy, 20-40% of cancer patients with systemic pathology have or will develop brain metastases2,3. Most common brain metastases have their primary tumor in the lung (~45%), breast (20%) and skin (e.g. melanoma, 10%)4. Brain metastases have a very poor prognosis, being characterized by a progressive Central Nervous System (CNS) damage and functional decline, significantly affected quality of life and shortened patient survival. Advanced melanoma is well known for its potential to metastasize to the brain. Approximately 80% of the melanoma patients present brain metastases at autopsy5,6.
However, current therapies are not very efficient and brain metastases are in most of the cases lethal. Treatment of melanoma brain metastases with surgery and/or radiation therapy results in a median overall survival of only about 4-6 months after diagnosis and they cause notable complications and morbidity (stroke, radiationinduced necrosis and cognitive defects)7. New immunotherapies such as targeted or immunomodulatory drugs, many in clinical trials, have shown promise, with some immunomodulatory drugs being able to at least double the overall survival rates for patients with melanoma brain metastases8. Immunotherapy uses components of the body's own immune system to fight against cancer. It works in several ways, for example by enhancing the capacity of the immune system to attack cancer cells or giving the immune system specific components artificially produced9. In particular, immunomodulators, antibodies stimulating T-cell function either by blocking or activating regulatory receptors, have shown to cause regression of several types of tumors and an exponential number of clinical trials are underway. Several immunomodulatory drugs/ checkpoint inhibitors are already approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer, breast cancer, bladder cancer, kidney cancer, Hodgkin lymphoma10,11. Noteworthy, pembrolizumab was recently approved by the FDA for solid tumors with microsatellite instability-high (MSI-H) or mismatch repair-deficient11.
Here, we aim to review the most important advances and future potential of using immunotherapy, such as the newly developed immunomodulatory drugs, for melanoma brain metastases therapy.
2. Melanoma Brain Metastasis
Melanoma brain metastases have been detected in about 45-60% of the patients, with 75%-80% presenting brain metastases at autopsy examinations. MRI is the gold standard for both diagnosis and monitoring of brain metastases12. Patients diagnosed with melanoma brain metastasis have an overall survival of only 4 to 6 months with standard available treatments, such as surgery and/or radiation therapy13. This is definitely not the desired outcome and sustain efforts are currently underway to develop better therapies.
The tumor microenvironment is an important factor influencing all steps of metastasis development, from metastasis formation to its progression and response to different therapies. In addition to the tumor cells, tumor microenvironment also contains other types of cells, such as fibroblasts, immune cells, pericytes and endothelial cells. The main features distinguishing the brain tissue from any other tissues are the presence of blood-brain barrier (BB) and unique resident cells (microglia, astrocytes and neurons)14. Recent results suggest that tumor cells from brain metastases can communicate with local astrocytes through gap junctions and program them to produce and secrete tumor-stimulating cytokines. These cytokines will then promote NF-kB-mediated survival and/or proliferation of cancer cells. Gap junctions can be successfully targeted15.
Interestingly, the report of a functional lymphatic vasculature along dural sinuses in mice caused a revision of the previous view of CNS as an immune privileged site16,17. Moreover, CNS-derived antigens can induce an immune response in cervical lymph nodes18, while some reports show that the BB can be affected in brain tumors resulting in significant accumulation of immune cells from outside CNS19. Noteworthy, previous studies reported that the brain metastases, unlike normal brain parenchyma and primary CNS tumors, have an immunoregulatory environment significantly infiltrated by lymphocytes. For example, over 99.1% of the analyzed brain metastases in a study shown the presence of the CD3+ lymphocytes, with over 55% having high density of tumor-infiltrating lymphocytes20. This is in contrast with the early-stage brain tumors, which, at least in part, were previously shown to have an immunosuppressive environment, with no presence of peripheral immune cells21,22. Taken into consideration these results, it makes sense to consider immunotherapy as a potentially promising tumor-targeting strategy in melanoma brain metastases. Recent clinical trials have confirmed that his hypothesis is correct.
3. Current Treatments in Melanoma Brain Metastasis
Current therapies employed for brain metastases are generally inefficient, with very low median overall survival. They include whole brain radiation therapy (WBRT), surgery and stereotactic radiosurgery (SRS)23. WBRT is the standard treatment for metastatic brain tumors, with WBRT and surgical removal being used for multiple and/or large tumors and MRI-assisted SRI for smaller tumors. Tumor Treating Fields method is an additional option used in treating brain metastases24-27. Although successful, it may result in seizures and other CNS symptoms, such as insomnia or anxiety27.
Treatment of melanoma brain metastases with surgery and/or radiation therapy results in a median overall survival of only about 4-6 months after diagnosis and they cause notable complications and morbidity7 (Table 1). In general, SRS is preferred to WBRT in the treatment of melanoma brain metastasis28. Melanoma cells usually have a powerful DNA damage repair machinery, resulting in the need of delivery of larger fractions/doses of radiotherapy29. In contrast, chemotherapy has produced disappointing results in melanoma patients with brain metastases, and the results are similar to those obtained in melanoma treatment in general30.
Table 1. Current Treatments in Melanoma Brain Metastasis.
| Treatment | Most Important Side Effects |
|---|---|
| Whole-body radiotherapy | Radiation toxicity Headaches Nausea Vomiting Bone marrow suppression Skin reactions Fatigue |
| Stereotactic radiosurgery | Neurocognitive decline Brain swelling Fatigue Skin problems Local hair loss Nausea Vomiting Headaches |
| Surgical resection | Repeated surgical traumas Pain Fatigue Infections Organ dysfunction Appetite loss |
| Brachytherapy | Damage of brain tissue Brain swelling |
More promising results were obtained with targeted treatments in patients presenting BRAF activating mutations. For example, vemurafenib, dabrafenib or dabrafenib in combination with trametinib are FDA approved for metastatic melanoma patients that show the BRAFV600 mutation31,32 (see Table 2, Targeted Therapies).
Table 2. FDA Approved Drugs for Melanoma Treatment.
2-5,8,20-36 GM-CSF - granulocyte-macrophage colony-stimulating factor; IL-2 - Interleukin 2; cuSCC - cutaneous squamous cell carcinoma;
| Treatment | Mechanism of action | Effectiveness | Side Effects |
|---|---|---|---|
| IMMUNOTHERAPY | |||
| Talimogene Laherparepvec (T-VEC) | Virus-mediated GM-CSF production (genetically modified live oncolytic herpes virus) | 16.3% decrease in tumor size versus 2.1% in patients treated with GM-CSF; however, it does not improve overall survival; no effect on metastatic melanoma (e.g. brain metastasis) | Chills Fever Nausea Flu-like symptoms |
| Aldesleukin | Cytokine, targets the IL-2/IL-2R pathway | Effective in patients with advanced melanoma | Rash, Diarrhea Chills, Nausea |
| Peginterferon Alfa-2b | Cytokine, targets the IFNAR1 pathway, antiangiogenesis, direct action on tumor growth, allows interferon to stay longer in the blood | Efficient in delaying or preventing relapse of melanoma; however, it has no benefit on overall survival | Flu-like symptoms Fever Chills Headache Nausea Vomiting |
| High-dose Interferon Alfa-2b | Cytokine, targets the IFNAR1/2 pathway, antiangiogenesis, direct action on tumor growth | Effective prevention of melanoma relapse from 0.98 years to 1.72 years, 46% of patients taking it have five year-survival compared to 37% for those who did not take; it is the only approved drug for late stage IIB or IIC melanoma | Acute flu-like symptoms Nausea Vomiting Loss of appetite Low white and red blood cell counts |
| Pembrolizumab | Checkpoint inhibitor, targets the PD-1/PD-L1 pathway | At a dose of 2mg/kg, 24% of patients had their tumor shrink for about 1.4 to 8.5 months; similar effect at a dose of 10mg/kg; included in the adjuvant (pre-surgical) setting | Fatigue Cough Nausea Severe itching, Rash Joint pain |
| Nivolumab | Checkpoint inhibitor, targets the PD-1/PD-L1 pathway | 35% reduction on the risk of recurrence or death in patients with stage III melanoma; 45% reduction in the risk of disease progression in patients with stage IV melanoma | Rash Pneumonitis, Colitis, Hepatitis Muscle or joint pains Muscle weakness Headache, Dizziness |
| Ipilimumab | Checkpoint inhibitor, targets the CTLA-4 pathway | First-line therapy for subsets of patients with advanced melanoma | Fatigue Diarrhea Itching, Rash |
| Combined Nivolumab and Ipilimumab Regimen | Targets both PD-1/PD-L1 and CTLA-4 pathways | 58% of patients had a three-year overall survival rate compared to 52% to those who only took nivolumab; However, the toxicity tripled with the combination | Rash, Itching Headache Vomiting Colitis, Diarrhea |
| TARGETED THERAPIES | |||
| Vemurafenib | Kinase inhibitor, blocks activity of V600E-mutated form of BRAF (protein helping the growth of melanoma) | About 50% of patients had their tumor shrink compared to 5% who received DTIC; Progression free-survival was 13.6 months compared to 9.7 months for patients on standard chemotherapy; On clinical trials, 77% of patients were still alive compared to 64% of those taking DTIC | cuSCC (24%) Severe allergic reaction Skin rash Photosensitivity reaction Joint discomfort Uveitis |
| Trametinib | Kinase inhibitor, blocks the activity of V600E and V600K mutated form of BRAF (key protein helping the growth of melanoma) | On phase III of clinical trial, progression-free survival was 4.8 months compared to 1.5 months for patients on chemotherapy; 22% of patients had their tumor shrink compared to 8% for chemotherapy | Skin rash (87%) Heart failure Shortness of breath Cough Blindness Blurred vision High blood pressure |
| Dabrafenib | Kinase inhibitor, blocks activity of V600E-mutated form of BRAF (key protein helping the growth of melanoma) | Progression free-survival was 6.9 months compared to 2.7 months for patients on standard chemotherapy; on phase III clinical trial, 52% of patients had their tumor shrink compared to 7% who received dacarbazine | cuSCC Primary melanoma Serious fever Diabetes Hair loss |
| Combined Trametinib and Dabrafenib Regimen | Blocks some mutated forms of BRAF and MEK kinases (proteins helping the growth of melanoma) | On stage III, 53% decreased risk of disease recurrence or death; on stage IV, after 1 year of treatment, the overall survival was 73% compared to 64% in vemurafenib therapy; after 2 years, 51% of the patients were still alive compared to 38% taking vemurafenib alone; progression-free survival was 12.6 months versus 7.3 months | Skin rash Higher incidence for basal cell carcinoma Primary melanoma Serious fever Hemorrhage Heart failure Blood clots |
| Combined Encorafenib and Binimetinib | Blocks some mutated forms of BRAF and MEK kinases (proteins helping the growth of melanoma) | Progression-free survival was 14.9 months compared to 7.3 months for the patients treated with vemurafenib alone; only 5% of patients stopped the treatment due to adverse reactions | Fatigue Nausea Diarrhea Joint pain/swelling Abdominal pain |
| Combined Cobimetinib and Vemurafenib Regimen | Blocks activity of V600E-mutated form of BRAF and MEK kinases (proteins helping the growth of melanoma) | Progression-free survival was 12.3 months compared to 7.2 months for the patients treated with vemurafenib alone; 65% of patients were alive 17 months after the beginning of treatment compared to 50% of those taking vemurafenib alone | Diarrhea Photosensitivity reaction Nausea Vomiting Fever |
| CHEMOTHERAPY | |||
| Dacarbazine | Anti-mitotic; anti-metastatic | 5-20% of patients with stage IV melanoma had their tumor shrink or growing slowly; however, it doesn’t improve progression-free or overall survival; it’s the only approved drug to treat metastatic melanoma | Allergic reactions Blood problems Nausea, Vomiting Diarrhea Flu-like symptoms |
However, although these targeted inhibitors are effective when used, resistance emerges in most of the treated cases. Resistance occurrence in melanoma brain metastases is not well studies and the specific CNS environment may contribute to different resistance mechanisms compared to the mechanisms already described in melanoma located outside the brain35,36.
In recent years, already FDA approved or in clinical trials immunotherapies have shown significant promise, with several immunomodulatory drugs being able to at least double the overall survival rates for patients with melanoma brain metastases8. These therapies may potentially be improved by radiation37 and they may have decreased adverse effects (e.g. decreased neurotoxicity)38.
4. Immunotherapy in Metastatic Melanoma Tumors
Current FDA approved treatment for melanoma are summarized in Table 2. Three of the most important targeted therapies used in the clinic are vemurafenib, trametinib, dabrafenib and some of their combinations, which are FDA approved regimens for melanoma treatment acting by blocking BRAF with activatory mutations, such as V600E or V600K. Notable, the chemotherapy treatment is ineffective, with only 5-20% of patients having their tumor shrink, but with no improvement in overall survival, although it was the only approved drug to treat metastatic melanoma (Table 2).
The first immunotherapeutic to show effect against melanoma brain metastasis was high dose interleukin 2 (hdIL-2). Melanoma patients with CNS involvement require higher doses of IL-2, which is challenging due to adverse events such as neurotoxicities and the need for hydration39. Recently, several immunomodulatory drugs were approved for melanoma treatment, with a recent study showing that the checkpoint blockade immunotherapy can double survival rates for patients with melanoma brain metastases8. Patients receiving these immunomodulatory drugs showed a mean survival of ~12.5 months compared to ~5.2 months for those not receiving immunotherapy, with a 4-year survival of ~28% versus only ~11%8,40.
Research studies have demonstrated the CD4 and CD8 are required for limitation or prevention of brain metastases, with an important role assigned to the regulatory T cells (Treg)41. The most important molecules as immune checkpoints are the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4). PD-1 is found on the T cells and its interaction with PD-L1 expressed on the cancer cells surface, causes apoptosis of cytotoxic T lymphocytes, while preventing apoptosis of Treg cells42. In addition, CTLA-4 is a co-stimulatory protein which interacts with receptors on T lymphocytes, inhibiting effector T cells.Both pathways are significant modulators of immune-tumor interaction (Figure 1) and targeting them focused significant energy in the past several years, with notable successes38.
Figure 1. PD-1 and CTLA-4 checkpoint pathways.
This figure presents the ligand-receptor interaction between tumor/APC cells and T cells, and activation of the PI3K-Akt, Ras-ERK and PLCy pathways inside the T cells.
Stimulation of T cells in the periphery with immunomodulators have also benefic effects against CNS tumors. A recent study has shown that pembrolizumab-induced PD-1 inhibition results in 20-30% responses in CNS, in patients with melanoma of non-small lung cancer CNS metastases. Moreover, combined regimen of nivolumab and ipilimumab, which acts by both inhibiting PD-1 and CTLA-4 has notable 55% CNS response in melanoma brain metastases patients38. Additionally, radiation therapy (e.g. SRS) is known to sensitize melanoma brain metastases to the action of checkpoint inhibitors, such as ipilimumab43. It is important to point out that, currently, there are several clinical trials underway for melanoma brain metastasis. A summary of the most important clinical trials is presented in Table 3. Immunomodulatory drugs, such as PD-1/PD-L1 or CTLA-4 inhibitors, have a great therapeutic potential in metastatic melanoma, including melanoma brain metastases. Noteworthy, only a small percentage of the patients are actually responding to these immunotherapies, with a high percentage of resistant cases. Thus, significant research has to be further performed in order to clearly define which patients respond to immune checkpoint inhibitors and how to sensitize the non-responders to these therapies.
Table 3. Clinical Trials in Melanoma Brain Metastasis.
Clinicaltrials.gov; SRS: stereotactic radiosurgery, WBRT: whole brain radiation.
| IMMUNOTHERAPY | PHASE | TRIAL | NAME OF THE TRIAL |
|---|---|---|---|
| Pembrolizumab (anti-PD-1 antibody) plus Bevacizumab (anti-angiogenic) | II | NCT02681549 | Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer |
| Pembrolizumab | II | NCT02886585 | Pembrolizumab In Central Nervous System Metastases |
| Pembrolizumab | II | NCT02085070 | MK-3475 in Melanoma and NSCLC Patients With Brain Metastases |
| Nivolumab (anti-PD-1 inhibitor) | II | NCT02621515 | Nivolumab in Symptomatic Brain Metastases (CA209-322) |
| Fotemustine (alkylating agent) Fotemustine and Ipilimumab (anti-CTLA-4 inhibitor) Ipilimumab and Nivolumab | III | NCT02460068 | A Study of Fotemustine (FTM) Vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis (NIBIT-M2) |
| Nivolumab vs. Nivolumab with Ipilimumab | II | NCT02374242 | Anti-PD 1 Brain Collaboration for Patients With Melanoma Brain Metastases (ABC) |
| Nivolumab plus Ipilimumab followed by Nivolumab monotherapy | II | NCT02320058 | A Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain Treated With Nivolumab in Combination With Ipilimumab Followed by Nivolumab by Itself (CheckMate204) |
| TARGETED THERAPY | PHASE | TRIAL | NAME OF THE TRIAL |
| Dabrafenib (BRAF inhibitor) plus Trametinib (MEK1/2 inhibitor) | II | NCT01978236 | Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets, Biomarkers and Metabolites |
| Buparlisib (pan-PI3K inhibitor) | II | NCT02452294 | Buparlisib in Melanoma Patients Suffering From Brain Metastases (BUMPER) |
| Abemaciclib (CDK4/6 inhibitor) | II | NCT02308020 | A Phase 2 Study of Abemaciclib in Patients With Brain Metastases Secondary to Hormone Receptor Positive Breast Cancer, Non-small Cell Lung Cancer, or Melanoma |
| WP1066 (STAT3 pathway inhibitor) | I | NCT01904123 | A Phase I Trial of WP1066 in Patients With Recurrent Malignant Glioma and Brain Metastasis From Melanoma |
| Dabrafenib (BRAF inhibitor) plus Trametinib (MEK inhibitor) | II | NCT02039947 | Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain |
| Vemurafenib (BRAF inhibitor) plus Cobimetinib (MEK1/2 inhibitor) | II | NCT02537600 | Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis (CONVERCE) |
| RADIATION PLUS SYSTEMIC THERAPY | PHASE | TRIAL | NAME OF THE TRIAL |
| Dabrafenib (BRAF inhibitor) plus SRS | II | NCT01721603 | A Phase 2 Prospective Trial of Dabrafenib With Stereotactic Radiosurgery in BRAFV600E Melanoma Brain Metastases |
| Nivolumab (anti-PD1 antibody) plus SRS | Pilot | NCT02716948 | Stereotactic Radiosurgery and Nivolumab in Treating Patients With Newly Diagnosed Melanoma Metastases in the Brain or Spine |
| Pembrolizumab (anti-PD1 antibody) plus SRS | Pilot | NCT02858869 | Pembrolizumab and Stereotactic Radiosurgery for Melanoma or Non-Small Cell Lung Cancer Brain Metastases |
| Ipililumab (anti-CTLA-4 antibody) plus SRS | II | NCT02097732 | Ipilimumab Induction in Patients With Melanoma Brain Metastases Receiving Stereotactic Radiosurgery |
| Ipilimumab (anti-CTLA-4 antibody) plus WBRT | II | NCT01703507 | Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma |
| Ipilimumab (anti-CTLA4 antibody) plus WBRT | II | NCT02115139 | GEM STUDY: Radiation and Ipilimumab in Patients With Melanoma and Brain Metastases |
5. Challenges and Limitations
Treatment of melanoma brain metastases with surgery and/or radiation therapy results in a very low median overall survival and there are important complications and morbidity associated with these treatments, with a prominent cognitive decline (see Table 1). For example, WBRT can result in radiation toxicity, headaches, nausea, vomiting, bone marrow suppression, skin reactions, fatigue, while SRS is usually associated with neurocognitive decline, brain swelling, fatigue, skin problems, local hair loss, nausea, vomiting, headaches (Table 1). Focal treatments such as SRS and surgery are limited to the treatment of the area of interest, which may result if tumor relapse from other not treated sites which were under the limit of detection of our imaging methods25.
Resistance to radiation, chemotherapy, targeted treatments and recently developed immunotherapies is one of the major challenges in treating melanoma, melanoma brain metastases and other types of malignancies. For example, in the case of immunotherapy, a significant number of patients do not respond to existing immunotherapy treatments, and the exact causes are under investigation38. Brain metastases are generally resistant to cancer immunotherapy. An extensive understanding of these mechanisms and causes of resistance for brain metastases is required in order to overcome this resistance. One limitation to these investigations are the current methods used to investigate the tumor and in situ tumor microenvironment of the brain, which provide limited information of a heterogeneous tissue, spatially and dynamically, in time27. Another limitation is the lack of preclinical models which can mimic with high accuracy human brain metastases and that can recapitulate all the steps of brain metastases development12. As some research group suggest, the development of intravital microscopy technologies for high resolution imaging of brain metastases can be an important step forward27.
The majority of patients with melanoma brain metastases will receive some form of radiation therapy. Thus, it is important to investigate how radiotherapy interferes with targeted and immunotherapy. Although initially the radiation treatment was believed to be immunosuppressive, recent studies showed that it can actually serve a booster of the anti-tumor immune response, by increasing the availability of antigens available after radiation-induced necrosis and other mechanisms. Noteworthy, the combination of radiation with immunomodulatory drugs is more efficient than the use of each drug alone38.
It is now imperative to detect better biomarkers within the CNS which can guide the therapeutic strategy and can predict the response to therapy, in particular immunotherapy. For example, some studies show that higher density of CD3 and CD8 tumor-associated lymphocytes is a good prognostic factors correlated with increased survival38. Additionally, some treated patients with brain metastases may need control of their symptoms with steroids, which can make immunotherapy ineffective38. In conclusion, there are many challenges and limitations to overcome in order to better investigate, understand, develop effective therapies and significantly treat melanoma brain metastases.
6. Conclusion
Melanoma patients with metastatic brain tumors have very poor prognosis. However, recent therapeutic strategies, such as the use of immunomodulatory drugs, are now emerging, with several compounds already approved by the FDA and other ones in clinical trials. Immunotherapy has already revolutionized the treatment of melanoma and other malignancies, with very effective results and low adverse events for some of the treated patients. However, many of the patients are resistant to immunotherapy and it is imperative to find out the exact mechanisms and how the tumor can be rendered sensitive. The preliminary studies in melanoma brain metastasis show significant promise and require additional investigation. In conclusion, immunotherapy and immunomodulatory drugs bring a great promise as new tools for melanoma treatment in particular and for the treatment of other types of malignancies in general.
KEY POINTS
◊ Some immunomodulatory drugs are able to at least double the overall survival rates for patients with melanoma brain metastases
◊ Immunotherapy, including the immunomodulatory drugs, bring a great promise as new tools for melanoma treatment in particular, and for the treatment of other types of malignancies in general.
Acknowledgments
The author is thankful to the Comenius University, Bratislava, Slovakia.
Footnotes
Conflict of interests: The author has no conflicts of interest to disclose.
Central Nervous System (CNS); US Food and Drug Administration (FDA); microsatellite instability-high (MSI-H); blood-brain barrier (BBB); programmed cell death protein 1 (PD-1); cytotoxic T lymphocyteassociated protein 4 (CTLA-4).
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